Hormones Flashcards
What nutrients contribute to proper production of thyroid hormones?
Iron, iodine, tyrosine, zinc, selenium, vitamin E, B2, B3, B6, C & D
Zinc & selenium increase conversion of T4 to T3
What factors can inhibit proper production of thyroid hormones?
Stress Infection Trauma Radiation, medications Fluoride (iodine antagonist) Toxins: pesticides, lead, mercury, cadmium Autoimmune disease - celiac
What can improve cellular sensitivity to thyroid hormones
vitamin A, exercise, zinc
What factors can increase conversion of T4 to rT3?
Stress, trauma, low-calorie diet, inflammation, toxins, infections, liver or kidney dysfunction, certain medications
What supplements can be given routinely in a hypothyroid patient?
Selenium (200-400mcg) Zinc (15-30mg) Vitamin D (2000IU) Vitamin A (2000IU) Iodine (150mcg) Iron (15-20 mg, in menstruating women; aim for ferritin of 50-100ng/mL)
What are some functions of cortisol?
Stimulates liver to convert amino acids to glucose and increase glycogen production
Mobilizes fatty acids into the blood
Increases coagulation
Suppresses parts of the inflammatory response
Prevents loss of sodium in the urine
Maintains resistance to stress, mood & emotional stability
What happens with chronic stimulation of cortisol production?
Stimulation of fat deposits Increases in blood pressure & blood sugar Increases in protein breakdown Bone demineralization Immune suppression Memory loss (hippocampus) Depression
What happens with chronic stimulation of catecholamine production?
Anxiety, depression
Increased CV risk factors - HTN, myocardial dysfunction
What are the 3 stages of Selye’s General Adaptation Syndrome? And the associated cortisol/DHEA lab findings?
Stage 1 - Arousal: cortisol & DHEA increase with episodic stress, but recovers to baseline. Asymptomatic, stimulated
Stage 2 - Adaptation: cortisol chronically elevated, DHEA declines; associated w/”stressed”, anxiety attacks, mood swings, depression
Stage 3 - Exhaustion: adrenal insufficiency w/low cortisol & DHEA; associated with depression & fatigue
What can disrupt hormonal balance?
Think STAINS
Stressors Toxins Antigens, allergens, adverse food reactions Inflammation Nutrition Inadequate Sleep
Genetics, nutritional insufficiency, insulin imbalances, poor diet, alcohol, smoking, food reactions, dysbiosis, hyperpermeability, B-glucoronidase, poor sleep, acute/chronic stress, adiposity, altered biotransformation, poor methylation, inflammation, infection, trauma, toxins
Which enzyme converts pregnenolone & progesterone towards sex hormone pathways?
What upregulates it?
17a-hydroxylase
Increased activity with hyperglycemia, hyperinsulinemia & PCOS
Which enzymes converts androstenedione and testosterone to estrone (E1) and estrone (E2), respectively?
What upregulates it?
What reduces it?
Aromatase
Increased activity w/alcohol, zinc deficiency, stress, hyperinsulinemia, cortisol, inflammation
Decreased w/lignans, soy, resveratrol, grape seed extract, proanthocyanidins, green tea, gingko, quercetin, vitamin C, stinging nettle, chrysin, metformin, beta sitosterol, progesterone
Which enzyme converts testosterone to dihydroxytesterone (DHT)?
What upregulates it?
What inhibits it?
5a-reductase
Upregulated by hyperinsulinemia
Inhibited by bee venom, Pygeum Africanum, stinging nettle root, soy
What enzyme is responsible for methylating 2-OHE1 and 4-OHE1?
What upregulates it?
What inhibits it?
Catechol-O-methyltransferase (COMT)
Upregulated by 5-MTHF, methylcobalamin, P5P, SAMe, Mg
Inhibited by soy, estradiol
What enzyme converts estrone (E1) to 2-OHE1?
What upregulates it?
What inhibits it?
Cytochrome 1A1
Upregulated by crucifers, berries, I3C, DIM, soy, flaxseed, quercetin, rosemary, exercise
Inhibited by OCPs, SAD, hops
What does PTSD stand for?
Production
Transport
Sensitivity
Detoxification/excretion
What is the order of treating hormone imbalances?
Adrenal -> thyroid -> sex steroids
What can cause testosterone deficiency? (ATMs)
Obesity, MetSx/DM2, sleep loss, stress, medications (chronic opioids, TCAs, glucocorticoids), cadmium, genetics (Kleinfelters XXY, Kallmann syndrome), tumors (prolactinoma), infiltrative diseases (hemochromatosis, amyloidosis), AIDS/HIV
Also prevalent in men with HTN and hyperlipidemia
What conditions can result from low testosterone?
Higher rates of MetSx, Type 2 DM Increased CV mortality Osteoporosis Sarcopenia Central obesity Cognitive decline (amyloid precursor protein dependence receptors on neurons and testosterone trophic effects) Low mood and energy ED
How to screen for low testosterone?
Birth history, maternal exposure, toxin exposure
Puberty & sexual development hx
Past or present major illnesses, nutritional deficiencies
Hx of depressed mood
Cardiometabolic disease
Changes in body characteristics (e.g gynecomastia)
What tests may be used to identify low testosterone?
Low total testosterone, early morning (ie <300ng/dL)
Also free T, SHBG, prolactin, LH, FSH to confirm and identify source of problem
What are interventions to increased testosterone production?
Weight loss, exercise (resistance + others)
Nutritional support w/vitamins A & D, Zinc
Optimize sleep (optimizes GH pulses and T in deep sleep)
Stress management
Cadmium detox w/Se, Zn, GSH, NAC, antioxidants; intestinal metal binders (silica, thiols)
How can we increase the sensitivity of androgen receptors?
Exercise - increase receptor density in skeletal muscle
Vitamin A
Manage E2 (as it increases dihydrotestosterone receptors in the prostate)
What can drive estrogen dominance?
ie high estrogen relative to low progesterone
Obesity & BMI, WHR (adipose tissue has aromatase and makes estrogen)
Upregulated aromatase
Environmental: Xenoestrogens/Endocrine disruptors, POPs, estrogens fed to cows
Caffeine
Alcohol
Gut dysbiosis
Stress, cortisol
Iatrogenic (OCP, HRT)
Impaired liver function
Nutrient deficiencies that impair ovarian and/or mitochondrial function
Lack of phytoestrogens
Too much sugar and refined starches (increases insulin and androgen production)
What can drive luteal phase dysfunction?
ie. low progesterone and luteal phase <11 days
Stress, low fat diet, energy deficit, excessive exercise, PCOS
What can drive hormonal insufficiencies in women?
Aging, menopause, premature ovarian failure, nutritional deficiencies
What can drive sub-optimal hormone metabolism?
ie. sub-optimal 2,4,16-OH-estrogen
SNPs (eg for COMT, GST, CYP enzymes) Poor diet, alcohol HRT Endocrine disruptors PCOS
Which estrogen metabolites are carcinogenic?
16a-OH-estrone
quinone (from 4-OH-estrone) - neutralized by GST enzyme
Note: 2-OH-estrone has minimal estrogenic effect and is the preferred metabolite; 16a-OH-estrone is similar estrogenic effect as estradiol
What are symptoms of low thyroid function?
Memory & concentration problems, headaches, migraines, constipation, gas/bloating, low libido, reactive hypoglycemia; SIBO symptoms
Fatigue, weight gain, cold, dry hair and skin, hair loss, edema, muscle and joint aches, depression;
Possibly low waking axillary temperature
What tests should be done for thyroid assessment?
TSH, T3, T4, RT3, TT3, TT3/RT3, FT3/FT4, Thyroid Antibodies (TPO, thyroglobulin)
Iron, RBC zinc, selenium: RBC selenium, whole blood glutathione, vitamin D, serum vitamin A, urinary morning fasting iodine spot, celiac screening, food sensitivities, toxic minerals (RBC)
What therapies are used for thyroid replacement?
Levothyroxin
Liothyronine
Standardized porcine thyroid glandular (4 parts T4, 1 part T3)
Compounded thyroid with various ratios of T4/T3
What are some environmental toxins associated with thyroid toxicity?
PCBs, BPA, triclosan, PBDEs have direct effects on thyroid receptor
Organochlorine pesticides, dioxins activate hepatic enzymes and reduce T4 half-life
Hg associated with elevated TgA
increase fluoride exposure? (especially with iodine deficiency)
Which thyroid enzymes require selenium?
What is recommended supplementation?
The selenoproteins: Deiodinases & glutathione peroxidase
Give: Selenomethionine 200ug daily
Note - selenium level is also inversely correlated with thyroid antibody and TSH levels
Which thyroid enzyme requires iron?
Heme-dependent thyroid peroxidase
Aim for ferritin above 100ug/L or 100ng/mL for symptomatic improvement
How does black cumin (nigella sativa) help with thyroid function?
1g BID decreased TPO antibodies, TSH and increased T4
Helps with thyroid gland repair, antioxidant, and immunomodulatory
What is the mechanism of action for LDN?
What is the recommended dosing for autoimmune thyroiditis?
Displaces endorphins from opioid receptors leading to a rebound effect which causes endorphin production increase, increase receptor sensitivity, increased endogenous opioid production, anti-inflammatory;
Also reduce thyroid antibodies, increase T4 to T3 conversion, reduce conversion to rT3
Start w/0.5-1.5mg/day and increase up to 3-4.5mg/day over the course of 2-4 weeks
What are potential side effects of LDN?
Insomnia, vivid dreams
Anorexia, nausea, diarrhea, anxiety
Muscle pain, drowsiness
Why might some patients feel better with combination thyroid replacement therapy (levothyroxine + liothyronine) vs mono therapy with levothyroxine?
Persistent symptoms might be explained by the inability of levothyroxine to restore T3 levels in serum and all target tissues.
Genetic polymorphisms in the deiodinase 2 enzyme
What is the case for desiccated porcine thyroid? What’s the case against?
Contains all different types of thyroid hormone (T4, T3, T2, T1), which may have beneficial effects. Also includes thyroglobulin, iodine and glandular tissue which might have beneficial effects
BUT, supra physiological dose of T3, possible potentiation of auto-immunity (theoretical, no evidence of this)
What foods can reduce absorption of thyroid replacement therapy?
Coffee, soy, calcium, aluminum antacids, ferrous sulfate, possibly grapefruit
What is optimum TSH level?
0.4-2/2.5
What is the cortisol awakening response?
Salivary cortisol quickly peaks 30-45minutes post-awakening (separate from the increase that occurs during second part of the night)
- believed to be influenced by stress anticipation and reflects capability to cope with acute stressor
High CAR is a pre-clinical biomarker indicative of early adrenal dysregulation
What is the significance of a flat cortisol curve?
Loss of resilience; inability of HPA axis to recover from challenges
Note if very low and flat - consider organic pathologies like Addison’s, pituitary pathologies
What are symptoms of chronically elevated cortisol?
Anxiety, depression, irritability, fatigue, night sweats, sleep disturbances, carb & sweet cravings, weight gain, hypertension, brain fog (hippocampal atrophy), compromised immunity
Note vicious cycle: increased cortisol - decreases gut immunity - increases food sensitivities - increases cortisol
What are conditions associated with chronically elevated cortisol?
IBS-C, insomnia, migraine, MELANCHOLIC depression, CFS, PMDD, anxiety, bipolar
How does chronically elevated cortisol contribute to depression?
Desensitization of glucocorticoid receptors resulting in the inability to return to resting conditions. Prolongs receptor activation and the downstream effects
What are characteristics of melancholic depression?
Anxiety, dread of the future, insomnia, lack of appetite,, worse in AM
Treatment-resistant depression associated with hyperactive HPA-axis and elevated cortisol; SSRIs decrease this
What are symptoms of chronic LOW cortisol?
Fatigue (especially morning or after a stressor), anxious, panic attacks, emotional paralysis, apathy, lack of motivation, memory loss, poor concentration, allergies, depression (worse in pm), low blood pressure, poor sleep (awakenings), cravings of salty, sour or spicy foods, anorexia, nausea, early onset menopause, decreased immunity
What are conditions associated with LOW cortisol?
Atypical depression, seasonal affective disorder, panic attacks, post-partum depression, GAD, BAD, CFS
Associated with CFS and ACEs in women
What is atypical depression and how is HPA axis dysfunction associated?
Sx: lethargy, hyperphasic, hypersomniac, diurnal (best in AM)
HPA-axis hypoactivity
What pattern of HPA/cortisol is associated with PTSD?
Hyperactive central CRH system, but underactive HPA axis; enhanced cortisol suppression
But often mixed - hypo, hyper-cortisolemia
What is CV prognosis of flatter cortisol curves?
Increased CVD mortality
What are signs of high adrenaline?
Weight loss, anxiety, hot flashes, cold (compensatory hypothyroidism), muscle wasting (if not exercising), bone loss
What are signs of high cortisol to look for on physical exam?
Depression/anxiety weight around midsection elevated cholesterol sx of high adrenaline body shape change (increased inflammation with android type + high cortisol, high insulin; extreme gynoid - estrogen imbalance)
What are hormonal consequences of cortisol “steal”?
Low progesterone, leading to anxiety, PMS, PMDD, hypoadrenalism, PCOS
What are PE findings associated with HPA dysfunction?
Orthostasis, iris can’t hold contraction when light shined in eye, Sergent’s white line (line drawn on abdomen stays white for several minutes instead of turning red), Rogoff’s sign (tenderness over adrenal glands), melasma, swollen ankles
What nutritional deficiencies are associated with taste bud atrophy?
B2, B3, B12, iron
What are tests used to assess HPA axis?
Serum: ACTH, DHEA-S, pregnenolone
Saliva: cortisol, DHEA, cortisol/DHEA ratio, melatonin, sex hormones
What are some basic supplements to consider for adrenal health and why?
B-Complex: B1 - antistress effects B5 1000-1500mg - supports adrenal release of cortisol & progesterone B6/P5P 50-100mg Biotin 1000mcg Folate 400-800cg B12
vitamin C 1-2g & antioxidant blend: vit C associated with Tyr, Trp, catecholamine and carnitine metabolism
Mg 400-600mg
Omega-3 FA 1-3g (blunts stress response)
Zinc 20-50mg (decreased w/stress; functions in immunity, oxidative stress, decreases neuroprotective GABA)
What botanical adaptogens/anxiolytics are preferred for alarm, Stage 1 adrenal response? (ie hypercortisolemia)
Ashwagandha, holy basil, L-theanine, 5-HTP, Passion flower, Valerian, kava kava, Rehmanna, Schisandra, polygala
What botanicals can be used for Stage 2 adrenal response? (ie resistance phase, early decompensation; hypercortisolemia)
Ashwaghana, rhodiola, cordyceps, Siberian ginseng (Eleuthero), SJW (affects genes associated with HPA), phosphatidylserine, dark chocolate (increases urinary excretion of cortisol and catecholamines)
L-lysine, l-arginine
What are some lifestyle and nutrition ways to modulate a hypercortisol state?
Stress reduction
Low GI diet, with frequent meals and no stimulants
Exercise, adequate sleep
MVI w/extra Mg, B complex, C and omega-3
Phosphatidylserine (lowers cortisol, helps w/sleep)
Rhodiola (has anti-fatigue effect + reduces stress response; can have stimulating effects, so start at 100mg and titrate), Siberian ginseng
DHEA as needed
What botanicals may be used for Stage 3 adrenal response? (ie exhaustion; hypocortisolemia)
Ashwagandha, Licorice, Rehmannia, cordyceps, Asian/panax ginseng
Licorice: decreases cortisol effects, increases aldosterone
What is the mechanisms behind hypotension associated with exhaustion phase?
Aldosterone levels may decrease from cortisol steal (chronically elevated), leading to orthostasis; Tx temporarily with increase in salt intake until underlying issues fixed
For what conditions has DHEA been found to be useful?
post-menopausal osteoporosis, SLE, psychiatric disease, sexual dysfunction
+ exercise - improves physical functioning in women
topical - for menopausal vaginal atrophy
What are the functions of testosterone?
Tissue growth and repair Male reproduction Biomarker for comorbid diseases Immune modulation Adipocyte growth inhibition Energy metabolism Lipid and CVD health
What are the subtypes of testosterone deficiency?
Classical schema:
Primary = decreased T, increased LH/FSH (testicular failure)
Secondary = decreased T, decreased or normal LH/FSH/GnRH (pituitary or hypothalamic failure)
But - this schema doesn’t account for majority of men having clinical and biochemical low T
Adult onset hypogonadism: part of secondary, but without a known medical cause (70% of with this have metabolic disease)
How is low testosterone associated with aging? (ie mechanisms)
- More comorbitidities = higher prevalence of T deficiency w/age
- SHBG levels rise with age, causing decrease in free T
- relative ratio of testosterone/estradiol decreases in some men
- age-related T levels decline partly due to primary testis failure; also GnRH decreases and GnRH/LH pulse amplitudes drop
- increased fat = leptin resistance = decreased GnRH release
- blunting of diurnal T rhythm with men age >45yo
What inhibits 17,20-lyase? (conversion of 17-OH-pregnenolone & progesterone to DHEA & androstenedione… which ultimately convert to testosterone)
Hyperinsulinemia, stress, inflammation, licorice
Enhanced by meditation
What are possible mechanisms behind low T with obesity?
Obesity + fatty foods = intestinal permeability = LPS & metabolic endotoxemia = low grade inflammation and decreased T
Aromatase in adipose tissue causes peripheral conversion of T to estrogen, exerting a negative feedback effect on pituitary LH -> decreased T
“Heating” of testicles by pelvic fat tissue
Obesity-related oxidative stress
Adipokines (eg leptin) and pro-inflammatory cytokines
What toxins are associated with low testosterone?
Phthalates (in utero and post-natal), maternal bisphenol-A, cadmium, lead, mercury, PFOS (perflurooctanesulfonate), PBDE (flame retardants)
What toxins are associated with reduced male fertility?
Organophosphates, solvents, Pb, Hg, air pollution (vehicle exhaust, cigarette smoke), excessive alcohol, marijuana, phthalates, PCBs, pesticides
What are benefits of testosterone supplementation?
Increased fat-free mass (lean muscle), improved exercise endurance, improved balance, increased bone density, decreased abdominal fat, improved cognitive function, improved cardiac health and mortality benefits
What increases SHBG? (thereby reducing hormone availability)
Pregnancy, hyperthyroid, aging, hepatitis, HIV
Exogenous estrogens, anticonvulsants, vitamin D, BPA
Low fat diet, low protein vegetarian diet
What decreases SHBG? (thereby increasing hormone availability)
DM-2, obesity, MetSx, hypothyroidism, nephrotic syndrome
Insulin, IGF-1 & growth hormone, androgens, progesterone, prolactin
Stinging nettle, EPA/DHA, whey protein, glucocorticoids
What nutraceuticals, botanicals & Rx inhibit 5-alpha-reductase?
Saw palmetto, krill, omega-3, stinging nettle root, quercetin, chaste tree berry, black cohosh, green tea, flax seed, soy isoflavones, beta-sitosterols, progesterone, pygeum africanum, chrysin, l-lysine, zinc, pumpkin seeds, rice bran (Rx finasteride, dutasteride)
What nutraceutical, botanicals & Rx inhibit aromatase
Dietary fiber, lignans (flax seed), isoflavones, resveratrol, grape seed extract, white button mushrooms, green tea, quercetin, vitamin C, stinging nettle root, chrysin beta sitosterol, zinc, progesterone (Rx: anastrozole, ketoconazole, metformin)
What is the role of leptin in male hormone dysfunction?
Negative feedback on LH production - directly inhibits androgen synthesis in the testes. (in turn increases triglyceride uptake into adiopocytes)
Triglycerides induce leptin resistance by inhibiting leptin crossing the BBB and signaling satiety
What are ways to reduce leptin resistance?
Healthy fats to promote ketosis
Intermittent fasting
Lean/clean protein and insulin-sensitizing foods (veg, fiber)
Curcumin, CoQ10, ALA, berberine; Cr, Se, Mg, B vitamins, vitamin D3, vitamin C
Which nutrients are associated with improvements in androgen/testosterone and sperm production in men?
Vitamin A, vitamin E, zinc, selenium, vitamin D
With which mineral can the toxic effects of cadmium be ameliorated?
Selenium
Note Cadmium reduces SOD and GPx activity and reduce testosterone levels
What botanicals could be used to support testosterone, sperm and prostate health?
Pygeum, urtica dioica (stinging nettle), beta-sitosterols, pollen extract, onion, garlic; long Jack (mucuna), ashwagandha, fenugreek, nigella sativa, black maca (not red)
Tribulus?
What botanicals may be used for BPH?
Pygeum, beta-sitosterols, rye grass pollen, stinging nettle root, combo of saw palmetto + stinging nettle
What micronutrients are beneficial for prostate health?
Vitamin E (mixed tocopherols, but especially gamma), zinc, selenium (via selenized yeast), vitamin D, vitamin C
What foods are limited and encouraged in a healthy prostate diet
Limit: Arachidonic acids (meat, dairy) and BBQ, grilled, or processed meat
Eat: monounsaturated fats, omega-3s, isoflavones, green tea (3-6 cups), fruits and veg (5-9 servings), crucifers, lycopene
Why is testosterone replacement not recommended for young males desiring fertility?
Exogenous testosterone reduces pulsatile GnRH for spermatogenesis
Who are candidates for hCG supplementation in lieu of testosterone? (SC or troches)
Young men with hypogonadism desiring fertility, older men not wanting testosterone, responsive gonads
hCG acts like LH - stimulates Leydig cells to create testosterone without central GnRH suppression
What labs are used to assess testosterone deficiency?
Serum testosterone, free testosterone, DHEA-S, SHBG
Note salivary level correlate with serum free-T, but not endorse by Endocrine Society
What conditions are associated with higher risk of adverse outcomes of testosterone replacement therapy?
Metastatic prostate CA, breast CA, unevaluated prostate nodule, unevaluated high PSA, Hct >48%, severe LUTS associated with BPH, uncontrolled CHF, desire for fertility in the near future, thrombophilia, uncontrolled OSA, severe COPD, severe renal or hepatic failure, hypercalcemia, advanced age
What are potential side effects with testosterone therapy?
Acne, apnea, depression, edema, male pattern baldness, gynecomastia, low sperm, testicular atrophy, changes to libido, hepatitis, insomnia, polycythemia (stop if Hct>54);
Urology consult if abnormal DRE, increase in PSA (>4 or >1.4 increase in a year)
How should sex hormones be monitored while on HRT?
24-hr urine for metabolites, or 4-point dried urine collection
Saliva seems to be less reliable
Dried urine better for monitoring oral progesterone
Note - dried urine not good for SL/troche/drop HRT because confounded by swallowed hormone
Do not use capillary blood spot
What are roles of growth hormone?
Building and maintaining lean muscle mass, promotes lipolysis, improved bone mass, less atherosclerosis, better lipid profile
Note - supplementation only beneficial in elderly with low GH
What are some botanicals for chronic prostatitis?
Zinc, saw palmetto, rye grass pollen, star grass, agrimony, nettle root, quercetin, cranberry, uva ursi, marshmallow root, eryngo
Also: pelvic PT, transurethral microwave therapy, mind-body therapy, stress reduction, homeopathy, TCM, acupuncture
What mechanisms to optimizing testosterone?
modulate SHBG, aromatase, 5-alpha-reductase; test and optimize DHEA and LH
How does the gut impact estrogen potency?
Beta-glucuronidase from bacillus spp
Fiber binds excreted estrogens
Dietary estrogens and factors that impact CYP450 enzymes
Alcohol impacts liver metabolism
Liver: SHBG, drug and toxin competition for P450
Mycoestrogens and alcohol from yeast
What interventions can be used to improve gut function and estrogen metabolism?
Treat dysbiosis and bacillus overgrowth Calcium glucarate 500mg TID Ensure elimination (Mag citrate, fiber, water) Treat yeast Treat barrier function with glutamine Assess HCl and protein absorption 5-Rs
What conditions are associated with luteal phase dysfunction?
Infertility, first trimester miscarriage, short cycles, eating disorders, excessive exercise, stress, obesity, aging, PCOS, inadequately treated 21-hydroxylase deficiency, thyroid dysfunction, hyperprolactinemia
What are causes of luteal phase dysfunction?
Dietary: SAD, low fat diet, low calorie diet
Excessive exercise
HPATG axis dysfunction due to stress (cortisol steal)
What are some challenges to measuring peak progesterone levels?
Pulsatile progesterone secretion makes single measurements unreliable
Must know when ovulation occurs, as progesterone tends to peak 6-8 days after ovulation
Urinary pregnanediol not as variable, but represent sum of total progesterone since last void
What are ways to increase & support progesterone?
Improve insulin sensitivity
80mg/day progesterone cream (as effective as 200mg/day PO)
Lowering TSH levels increases progesterone
Weight loss
Eat organic meats raised without hormones
Vitamin C 750mg, E 600mg, B6 200mg/day
Black cohosh
What are 7 signs and symptoms of hormonal imbalance?
Fatigue, anxiety, weight gain or difficulty losing weight, insomnia, IBS, skin and hair changes, PMS & low sex drive
What are some pros and cons of serum estrogen hormone testing?
Pros: well validated, measures endogenous hormone production
Cons: Reflects both free and bound hormone, quantification challenging in postmenopausal
What are some pros and cons of saliva estrogen hormone testing?
Pros: non-invasive, correlates well with serum free estradiol
Cons: fewer validation studies, doesn’t capture metabolites, decrease salivary flow in post-menopausal
What are some pros and cons of spot urine estrogen hormone testing?
Pros: measures estrogen metabolites which are stable for a long time at room temp, measures both free and conjugated estrogens
Cons: requires good kidney function, least clinical validation studies, some metabolites are not clinically useful
What are pros and cons of using spot or 24-hr urine to measure progesterone levels?
Pros: Progesterone metabolite levels correlate well with clinical symptoms
Cons: progesterone not easily quantified in urine, limited validating literature
On what days should menstruating females have hormones tested?
Day 3-5: Estrogens, FSH, testosterone (free and total), SHBG, DHEA-S
Day 21-24: Progesterone, testosterone, SHBG, DHEA-S
What environmental toxins have been associated with early menarche?
DDT, PBDEs, PCBs, phthalates (estrogenic and anti-androgenic effects)
What is the functional approach to early menarche?
Minimize exposure to xenoestrogens
Maximize estrogen metabolism - NAC, I3C, B vitamins , vitamin C; artichoke, pomegranate, watercress, crucifers, onions, garlic, green tea
What are dietary interventions for PMS? (estrogen dominance, progesterone deficiency + stress)
Frequent small meals with low carbs, no processed foods and high quality fats (stabilizes sugars & cortisol)
Overall plant-based
Complex carbs (supports Trp transport into brain)
Calcium & vitamin D
No sugar, caffeine, alcohol
Mediterranean diet
Low fat, vegetarian diet: increases SHBG and decreases free estrogen; low fat reduces serum estrogen
Increased fiber
+ MVI & minerals, B complex, vitamin C, mag citrate, progesterone cream
How does vitamin B6 benefit PMS?
Cofactor for neurotransmitter synthesis (serotonin, dopamine, E/NE) - Note: Mg is also a cofactor
Anti-inflammatory (cofactor for synthesis of PGE1)
Glucose regulation - cofactor for using amino acids for gluconeogenesis
What botanicals may be used for PMS?
Curcumin
Chaste berry (caution with inducing estrogen ie fibroids, breast CA)
Ginger
What are causes of menorrhagia?
Hormonal imbalance, fibroids, high BMI, anticoagulants, problems with IUD, endometriosis, pelvic inflammatory disease, blood clotting disorder, vitamin A deficiency, uterine/ovarian/cerival cancer
What is the treatment strategy for menorrhagia?
Treat estrogen dominance Treat insulin resistance Treat inflammation Treat high levels of aromatase Detox protocols Optimize weight Address adrenal dysfunction Low dose cyclical progesterone Nutrients: methylated B vitamins, fish oil 2g/day, vitamin A, vitamin K, iron if needed; fiber
What botanicals may be used for menorrhagia?
To slow bleeding: Yarrow, Shepherd’s purse, cinnamon bark
To improve HPA-axis: chaste berry , Beth root, partridge berry
What botanicals may be used for dysmenorrhea?
Cinnamon bark, peppermint oil, cramp bark, ginger, valerian, Jamaican dogwood
Whats the functional approach to dysmenorrhea?
Treat, inflammation, leaky gut & dysbiosis
Treat estrogen dominance & high levels of aromatase
Detox
Low dose cyclical progesterone PO or topical
Matrix treatment
Stop sugar, elimination diet
Supplements: EPA/DHA, EPO 500mg TID, MVI, vitamin C, B complex & botanicals
How does insulin contribute to the pathophysiology of PCOS?
Elevated insulin:
- Alters hypothalamic function - more LH secreted, causing more androgen production and anovulation. Estrogen excess (not opposed by progestin)
- Decreases SHBG, leading to higher free testosterone
- Alters enzymes in the ovaries to produce more androgen, which further decreases SHBG
Also, increased androgens increase insulin
Note: dysbiosis theory on increasing insulin leading to PCOS (+ intestinal permeability, inflammation)
What botanicals may be used for PCOS?
Improve lipid profile: cinnamon, aloe vera, chamomile
Glucose control: cinnamon, chamomile, aloe vera, green tea, fenugreek
Hormonal support: milk thistle, fenugreek, green tea, spearmint, fennel, chaste berry
- resveratrol reduces androgens
Ovarian tissue: aloe vera, chamomile, green tea, spearmint, silymarin
How does myo-inositol work for PCOS?
A precursor to d-chiro-inositol; can use both synergistically
improves the way ovarian follicles use insulin and glucose (reduces insulin resistance at the ovary level, causing decreased testosterone precursors)
What is the functional approach to PCOS?
Low glycemic food plan, progesterone 100mg days 15-28, DHEA 5mg BID, vitamin D, vitamin C, B-complex, exercise, self-care, myo-inositol 4g/day, gut evaluation
What is the functional approach to infertility?
Nutrient dense pre-conception food plan Prenatal supplement + omega-3 Support insulin sensitivity Optimize body weight Screen for autoimmunity Manual pelvic physical therapy if needed Gut, adrenal and hormonal evaluation Treat the matrix Treat any underlying inflammation
What are adverse impacts of oral contraceptives?
Increased CVD, AI in some
Increased risk for depression
Increases thyroglobulin and decreases free thyroid
Increases SHBG -> decreases testosterone -> reduce libido
Potential liver toxicity
Nutrient depletions: folate, B6, B12, Mg, Zn, Se, omega-3s, Vitamins D,C,E; antioxidants
What are risk factors for early perimenopause?
Smoking (1-2 yrs earlier), family hx, cancer treatment, hysterectomy, autoimmune, toxins (endocrine disruptors, mycotoxins)
What are triggers for hot flashes (non-hormonal)?
Spicy foods, niacin, alcohol, caffeine
Meds: nitrates, Lupron, anti-hypertensives
Hyper or hypothyroidism
Adrenalin or cortisol (stress/anxiety)
Certain cancers (pancreatic, hormone-secreting cancers)
Hypoglycemia
Mycotoxins
Note: estrogen sets the rheostat, but adrenalin triggers the hot flash
What are some recommendations that can be made to reduce hot flashes?
Lower adrenaline and cortisol - treat insomnia, avoid hypoglycemia, reduce stress, exercise
Avoid excess sugar, caffeine, alcohol
Limit temperature fluctuations
Manage estrogen metabolism to minimize fluctuations
Acupunture
HRT - progesterone (helps with sleep, hot flashes, bones, CV health)
Supplements
GALS:
Gut, adrenals, liver/detox, receptor sensitivity (w/progesterone, SERMs, thyroid balance)
What supplements may be used for hot flashes and other perimenopausal symptoms?
Supplements:
Black cohosh (anti-estrogen, anti-oxidant, reduces sweating in breast CA)
Siberian rhubarb (SERM @ beta-ER)
Red Clover (isoflavone like soy)
Non-GMO soy (SERM @ beta-estrogen receptor and not alpha, which is proliferative)
Sage (flavonoids, anti-dopaminergic)
Note isoflavones good for hot flashes, bones, cognition, depression, breast CA prevention
How does progesterone therapy help with perimenopausal symptoms? What are the benefits?
Down-regulates E receptors, induces enzymes involved in E metabolism
Improves sleep, bone health, hot flashes, CV health, breast cancer risk (blocks estrogen receptor binding to DNA), menstrual symptoms (pain, heavy bleed), anxiety/mood swings, premenstrual migraines
How can progesterone be given for perimenopausal symptoms? What are potential side effects?
Don’t use synthetic MPA (this is a progestin, not progesterone, which is safer)
Oral micronized or topical progesterone qHS days 12-28
OTC/compounded: 100mg/mL - 1/4 mL applied to body part with little or no fat under the skin
Potential s/e: fluid retention, depression, irritability
How can hot flashes + irregular bleeding by managed? (a FxM plan)
Start with: 10-Day medical food detox smoothie w/tons of veg, flax + inositol powder Liver combo \+/- DIM, calcium d-glucarate pre/pro-biotic phosphatidylserine for sleep Limit caffeine, alcohol, sugars Self Care
Then:
Food plan - veggie Mediterranean or Paleo-style
Siberian rhubarb + black cohosh
Chasteberry 1000mg daily or progesterone therapy (2wks on, 2wks off days 14-18, or days 8-28 if post-menopausal)
Continue to limit caffeine, alcohol, sugars
Support hormonal pathways with methylated Bs, C, Se, Zn, Mg, Mn
Stress management
Sleep: phosphatidylserine, 5-HTP, melatonin, passion-flower, sleep hygiene
What are natural SEEM/SERMs?
Crucifers, fresh fruits and veg, legumes (soy, garbanzo), beans, raw seeds and nuts (flax), oat, whole grains, quality protein, oils (flax, olive, sesame), green tea catechins
What are biochemical/Rx inhibitors and enhancers to libido?
Inhibitory: opioids, serotonin, endocannabinoids, meds (anti-epileptics, hormonal, anti-hypertensives, statins, psychotropics, chemo, drugs of abuse)
Excitatory: dopamine, NE, oxytocin, melanocortins
How can DHEA be used to improve libido/sexual health?
Local application for vaginal atrophy
What precautions exist for testosterone use for libido?
- Can reduce SHBG and increase free estrogen -> increased breast CA risk (additive with excess insulin)
- a substrate for aromatase, making more estrogen
Efficacy for libido is modest - focus on correcting other factors (testosterone not recommended)
Which estrogen is weakest and has highest affinity for beta receptor?
Estriol (E3)
Can use vaginally for local symptoms
How can vaginal atrophy/dryness be treated?
Treat any chronic yeast (w/Abx, botanicals)
Coconut oil or water-based lubricants
Topical estriol daily x 6 weeks, then 2-3 x/wk
Vaginal DHEA
CBD-based oils/topicals to improve blood flow (note CBD inhibitory, THC stimulatory; lower marijuana dose better)
Estradiol, testosterone
Note: topical therapies - for lower 1/3 of vaginal for optimum responsiveness
What are the key foci for treating fibroids & endometriosis?
Reduce inflammation (IL1B and PGE2 are most potent aromatase stimulators driving fibroid growth; estrogen stimulates PGE2 via COX2 stimulation)
Reduce aromatase activity
Normalize vitamin D levels
Based on the theories that endometriosis may be caused by leaky gut, hormonal imbalances, inflammation, autoimmunity, toxins, etc - what can be done functionally to treat it?
Detox w/methylated Bs, catechins, NAC, silymarin, fiber, exercise, sweating
5Rs
Stress reduction
Balance estrogen & progesterone
Reduce excess insulin and visceral fat (inflammation)
How can excess estrogen be reduced?
Minimize aromatase-containing VAT
Address hyperinsulinemia (stimulates aromatase)
Aim for IBW and reduce hypo-adiponectin (which leads to insulin resistance and more estrogen)
Reduce PGE2 stimulation
Natural aromatase inhibitors (ie. soy, ligans, resveratrol, chrysin, grape seed extract, green tea etc)
Micronized progesterone to diminish E effect
Avoid dairy (or stick to low fat)
What are some nutraceuticals with epigenetic effects on cancer stem cells?
Folate, retinoid acid, butyrate, polyphenols (green tea, apples, coffee), soy (isoflavones, genestein), parthenolide (feverfew), curcumin, ECGC, I3C/DIM/sulforaphane (crucifers, garlic), lycopene, sirtuin activators (resveratrol), histone acetyltransferase inhibitors (ursodeoxycholic acid, etc), histone lysine methylation modulators (omega-3s), vitamin D, iodine, melatonin, essential oils (frankincense, myrhh), cannabinoids, turkey tail mushrooms
What are natural SEEMs? (selective estrogen enzyme modulators; found within the breast)
Resveratrol, genistein, lignans, curcumin, catechins, goji berries, EPA, isoflavones, DIM, quercetin, melatonin, black cohosh
Note: the numerous enzymes are unregulated by insulin resistance
What are strategies for reducing breast cancer risk?
Adequate iodine Vitamin D Reduce insulin resistance Increase SHBG (with plant-based diets high in SEEMs/SERMs) Reduce exposure to xenoestrogens
What can decrease the 2:16 estrogen ratio? (higher risk of cancer)
obesity, autoimmune, alcohol, pesticides, hypothyroid, high fat, low fiber, omega-6s, OCPs, estradiol-based HRT,
Also poor COMT, methylation or glutathione conjugation can lead to a more carcinogenic estrogen profile
How does alcohol impact breast cancer risk?
Increases risk, even if 1/day
Alcohol increases estrogen and decreases progesterone
Alters hepatic metabolism of estrogens (excess NADH inhibits breakdown of estradiol to estrone)
What are some natural interventions to support phase 1 estrogen metabolism and improve 2:16 ratio?
I3C, DIM flax lignans isoflavones (soy, Siberian rhubarb) weight loss, exercise omega-3s, curcumin, rosemary (antiinflammatories) Resveratrol No alcohol Lots of veggies Gogi berries Avoid pesticides, plasticizers, PAH Use Rx sparingly and at low doses
How to naturally support phase II estrogen metabolism? (ie methylation, glucuronidation, sulfation)
Methylation: activated folate, B6, B12, methionine, betaine (TMG), SAMe, MSM
Glucuronidation: beta-glucoronidase -> calcium d-glucarate, normalize microbiome, ground flax
Sulfation: glucosamine sulfate, MSM, NaSO4
Note: COMT catalyzes methylation (needs SAMe, Mg)
How to support excretion of estrogen metabolites?
Treat constipation and IBS Flax lignans EPA Magnesium to bowel tolerance Probiotics 5R Carminative herbs for bile production
How should HRT be timed to reduce CVD risk?
Start within 5 years of menopause and not >10yrs after, for women at high risk of CVD and low breast CA risk
What labs can be used to measure bone loss/OP?
DEXA
N-telopeptide
How does estrogen benefit bones?
Lowers bone sensitivity to PTH, reducing bone resorption
Increases production of calcitonin, inhibiting bone resorption
Increases calcium resorption by the intestines
Reduces renal calcium excretion
Direct binding to E receptors
How do progesterone and testosterone benefit bones?
Progesterone & dihydrotestosterone stimulate osteoblastic bone formation
How does estrogen impact cognitive function?
Increases BDNF and changes brain morphology (neuroprotective)
Possibly helps with memory consolidation
Improves cerebral blood flow and metabolic rate
Reduces ROS and protects mitochondria
What is the critical period hypothesis as it relates to HRT and cognitive function?
Estrogen must be given for 2-3 years starting at onset of menopause for lasting benefits
Progesterone (not progestin/MPA): promotes myelin and is neuroprotective
If started >65yo - higher risk of dementia
What is the functional Rx for osteoporosis?
5Rs Gluten-free, if indicated Absorbable calcium (citrate, hydroxyapatite, Ca + B, molybdenum, Mg, vitamin K, vitamin D Strontium? weight bearing and balance exercises E, P & T replacement
For whom is HRT contraindicated?
Undiagnosed genital bleeding, breast CA (including history), active embolism, hypercoagulation disorders, liver disease, pregnancy
For whom should HRT be proceeded with caution (but not C/I)?
Increased risk of breast CA:
Elevated estrogen levels (test)
Dense breasts (suggests reduced COMT activity/SNP?)
Increased leptin (enhances aromatase)
Genetic SNPs (COMT, MTHFR, CYP450 1A1, 1B1, 3A4, 3A5)
How can leptin be lowered?
Reduce overeating and VAT Omega-3s and other anti-inflammatories Curcumin & berberine Reduce stress Normalize insulin
What labs should be done before starting HRT?
Serum E2 DHEA-S Estrogen metabolites and methylation Insulin, glucose, leptin Cardio CRP
What are the substrates and products of 17,20-lyase?
pregnenolone -> DHEA & 17-OH-progesterone -> androstenedione
shunts away from cortisol production
What are the substrates and products of CYP3A4 in the metabolism of estrogen?
Estrone -> 16alpha-OH-estrone, estradiol -> estriol
What are the substrates and products of CYP1A1 in the metabolism of estrogen?
Estrone -> 2-OH-estrone
What are the substrates and products of CYP1B1 in the metabolism of estrogen?
Estrone -> 4-OH-estrone
Which enzyme shunts pregnenolone & progesterone towards the cortisol/sex hormone pathways (away from aldosterone production)?
17-alpha-hydroxylase
To what estrogen does testosterone convert to via aromatase?
Testosterone -> estradiol (E2)
How does stress directly and indirectly increase cortisol formation?
Pituitary increase of ACTH secretion
Slows down 17,20-lyase and decreases anabolism
Which enzyme is involved in stress-related cortisol steal?
11-beta-hydroxylase
What are possible exam findings with elevated cortisol?
Postural hypotension, pupil contraction, Sergant’s white lines (white line in abdomen w/blunt instrument forms and remains for several minutes), positive Rogoff’s sign (pain over adrenals w/pressure), swollen ankles
What is optimal range of TSH?
0.4-2/2.5
Which estrogen metabolites are carcinogenic and which enzymes help to detox them?
16-alpha-OH-estrone (detox by reductase to estriol)
4-OH-estrone (detox by COMT to 4-methoxy-estrone)
- also, 4-OH-estrone can be converted to carcinogenic quinones (detox with glutathione)
What is the FxM Rx to reduce endometriosis and fibroids?
Plant based, non-GMO, low inflammatory diet
Normalize insulin, reduce VAT
Improve GI function and integrity
Upregulate detox/metabolism
Decrease exposure to EDCs
Treat E2 dominance/P deficiency with progesterone (25-50mg topically, 100-200mg PO days 12/14-28 of cycle)
Reduce estrogen:
- Fix leaky gut w/5-Rs
- Correct functional abnormalities
- Supplements: MVM, 5-MTHF, garlic, probiotics (acidophilus & bifidobacter), silymarin, Mg, medical foods
- micronized progesterone 100mg PO or 12.5-25mg BID topically days 1-25 to diminish E effect
- eat organic, exercise, stress reduction, reduce VAT
What are risk factors for breast CA?
Lifetime estrogen exposure (ie late/no pregnancy, late menopause, early menarche, HRT>5yrs, OCPs)
Obesity, sedentary, personal/family Hx, atypical hyperplasia, dense breasts, radiation treatment, DES exposure, alcohol, smoking (esp in pre-menopausal)
